1. Field of the Invention
The present invention relates to a novel G protein having an ability of amplifying a signal transduction generated by a receptor upon binding to a natural ligand such as amine, peptide, hormone, autacoid, neurotransmitter and the like, as well as a polynucleotide encoding the same. The invention also relates to a method for screening for a substance which regulates the cellular signal transduction mediated by this novel G protein, and the like.
2. Description of the Background Art
A G protein is an important mediator in a signal transduction. Thus, the G protein serves as a transmitter which transport, into a cell, a stimulation signal received by a G protein-coupled receptor (hereinafter sometimes abbreviated as GPCR) which is a seven transmembrane receptor. A GPCR is expressed in a wide variety of tissues, and this signal transduction system was proven to be involved in regulation of a wide variety of cellular functions such as hormone reception, neurotransmission, cell proliferation and differentiation and the like (GENDAI KAGAKU ZOKAN 34, 61 to 70, 1997).
More specifically, a G protein is a heterotrimer formed from α subunit which binds to GTP, β subunit and γ subunit. When a GPCR on a cell membrane surface binds to a ligand such as a hormone or neurotransmitter, the GPCR is activated and its signal is transmitted to a G protein. In the G protein to which the signal has been transmitted, a GDP is released from the inactive form in which a GDP was bound once to the α subunit, and a GTP is then bound instead, whereby converting into an active form.
The active G protein is released from the GPCR while dissociating into a GTP-binding α subunit and βγ subunits. The active G protein promotes or inhibits its target effector such as adenylate cyclase, Ca2+ channel, K+ channel, phospholipase Cβ and the like, whereby regulating a variety of the cellular functions. A mammalian G protein α subunit may for example be Gi, Go, Gq, Gt and the like. Typically, a G protein α subunit is classified into any of 4 types, namely, the type which promotes the activity of an adenylate cyclase, the type which inhibits the activity of an adenylate cyclase, the type which promotes the activity of a phospholipase and the type which transmits a signal to a Rho.
A GTP which has been bound to an α subunit of an active G protein is converted into a GDP by the GTPase effect possessed by the α subunit, resulting in the recovery of an inactive form (“Signal Dentatsu”, p. 17-30, Nov. 1, 2001, KYORITSU SHUPPANSHA).
GPCR genes and its gene products and GPCR signal transduction pathway-related genes and its gene products are potential causes for diseases (Spiegel et al., J. Clin. Invest. 92: 1119-1125 (1993); MuKusick et al., J. Med. Genet. 30: 1-26 (1993); Lania et al., European J. Endocrinology 145:543-559(2001)). For example, a certain defect in a V2 vasopressin receptor gene as a GPCR has been proven to induce various forms of a nephrogenic diabetes insipidus (Holtzman et al., Hum. Mol. Genet. 2:1201-1204 (1993)). In addition, variation in Gα subunits are observed in a tumor of growth hormone secreting cells in a pituitary gland which secrets a growth hormone, hyperthyroid tumor, ovarian and renal tumors (Meij, JTA (1996), Mol. Cell. Biochem. 157:31-38; Aussel, C. et al., (1988), J. Immunol. 140: 215-220). Accordingly, GPCR signal-related gene products are useful as a target of a novel drug, and 50% of currently marketed pharmaceuticals were reported to direct the GPCR as a target (Nature Review Drug Discovery, 1, 7 (2002)).
Generally in screening natural ligands of GPCR, it is important to know which G proteins are to be coupled with the GPCR (Trends in Pharmacological Science, 22, 560-564 (2001)). Accordingly, identification of a novel G protein and a gene encoding the same is useful in treating or diagnosing a disease caused by the abnormality in the cellular signal transduction in which said G protein is involved. In addition, it can be used in the screening for a pharmaceutical which is useful as a remedial, therapeutic or prophylactic agent against a disease caused by the abnormality in a cellular signal transduction. Furthermore, it can be used in the screening for a pharmaceutical which is useful as a remedial, therapeutic or prophylactic agent capable of ameliorating or preventing a symptom by means of the activation or inhibition of the cellular signal transduction.